4-((4-((2-取代苯氧基)乙基)-1-哌嗪)-甲基)-1,2-二氢喹啉-2-酮类化合物的合成及体外α-受体拮抗活性

目的研究DDPH类似物1,2-二氢喹啉-2-酮类化合物的合成及其体外α-受体拮抗活性。方法通过酰化、溴代、环合和取代反应等合成目的物;推测了异常中间体3-溴-4-溴甲基-1,2-二氢喹啉-2-酮(5)和3-溴-4-甲基-1,2-二氢喹啉-2-酮(6)的生成机理;测定目的物的体外α-受体拮抗活性。 结果设计、合成了12个新化合物II_1～6和IV_1～6,其中6个目的物1,2-二氢喹啉-2-酮类(IV_1～6)的结构经IR,¹HNMR,MS和HRMS确证;IV₃,IV₄和IV₆对兔主动脉环抑制作用较明显。结论化合物IV₃,IV₄和IV₆显示了一定的抑制活性,值得进一步研究。     

可逆性胆硷酯酶抑制剂二甲氨基甲酸-5-二氢吲哚酯的合成

为了深入研究催醒宁类化合物的结构与抑酶活性的关系,设计合成了-系列1-,3-或5-位不同取代的二氢吲哚类衍生物(中间体和终产物共24个新化合物)。中间体1,3-二甲基-5-烷氧基-2-二氢吲哚酮(A)的C₃烷化。采用相转移催化方法进行;反应中还分离到三个副产物(Ⅶ～Ⅸ)。初筛结果表明:这些化合物大多有较强的抑酶活性;1,3-或5-位取代基的改变均明显影响其活性。     

d-生物素的不对称全合成研究

目的:探索工业生产可行的d-生物素的全合成方法。方法和结果:以(1S,2 S)-( + )-苏式-1-( 对硝基苯基)-2-氨基-1,3-丙二醇与顺-1 ,3-二苄基-四氢-4H-呋喃并[3,4-d] 咪唑-2,4,6-三酮(2) 缩合而成的顺-1,3-二苄基-5-[(1S,2S)-(+ )-苏式-1-羟甲基-2-( 对硝基苯基)-2-羟乙基]-四氢-4H-吡咯并[3 ,4-d] 咪唑-2,4,6-三酮(3) 经高立体选择性还原、水解内酯化成(3aS,6aR)-1 ,3-二苄基-四氢-4H-呋喃并[3 ,4-d] 咪唑-2,4(1H)-三酮(6),再经硫代、格氏反应、还原制成(3aS,6aR)-1 ,3-二苄基-4-羟基-4-(3-乙氧基丙基)-四氢-4H-噻吩[3,4-d] 咪唑-2(3H)-酮(9) ,后者经脱水、还原、裂解环合、脱苄4 步反应合成(3a R,8aS,8bS)-2-氧代-十氢咪唑并[4,5-c] 噻吩并[1 ,2-a] 锍鎓溴化物(12) ,继而缩合开环、水解即得d-生物素,以2 计算,总收率25-7 % 。结论:此法原料易得、操作简便、成本较低,适合工业化生产。     

3-[p-ω-取代氨基烃氧基)-苯甲酰]-吲哚衍生物的合成

本文根据某些吲哚化合物具有抗生育活性,结合多数非甾体抗生育化合物联有碱性醚链的结构特征,设计并合成了以吲哚为母核的四种类型化合物(Ⅰ_1～7,Ⅱ_1～7,Ⅲ_1～7,Ⅳ₁)22个,并验证了三个熔点与文献报道不符的关键中间体。对小白鼠的初步药理试验表明:所合成的化合物均无抗着床作用;Ⅱ₁,Ⅱ₂,Ⅱ₄和Ⅱ₅有明显的镇痛作用;Ⅲ₂和Ⅲ₃则有较强的抗电休克作用。     

6-(4-取代苯基)-4,5-二氢-3(2H)-哒嗪酮类化合物的合成及其抑制血小板聚集的作用

为了寻找较理想的抗血栓药物,本文设计合成了6-(4-取代苯基)-4,5-二氢-3(2H)-哒嗪酮类化合物16个。对ADP诱导的大鼠体外血小板聚集,均有不同程度的抑制作用。其中,化合物Ⅱ₂,Ⅱ3和Ⅱ₄的作用大于CCI-17810,又以Ⅱ₄的作用为最强。     

1-(1-取代苯基)-2-(1H-1,2,4-三唑或苯并三唑基)-O-(取代苄基)乙酮肟醚类化合物的合成及抗真菌活性

报道了29个新的1-(1-取代苯基)-2-(1H-1,2,4-三唑或苯并三唑基)-O-(取代苄基)乙酮肟醚类化合物的合成与体外抗菌试验。结果表明,大多数化合物对大部分真菌有抑菌活性,化合物T₁,T₄,T₆,T₁₁,T₁₂,B₁,B₃,B₄和B₆对部分真菌抑菌活性优于或相当于奥昔康唑。     

6-(4′-取代酰胺基苯基)-4,5-二氢-3(2H)-哒嗪酮类化合物的合成及其抑制血小板聚集作用

目的：6-(4′-取代苯基)-4,5-二氢-3(2H)-哒嗪酮类化合物的合成及抗血小板聚集活性的研究。方法：通过付-克反应、碳链延长、水解和环合反应得到两个关键中间体,然后通过酰化反应制得各种酰胺化合物;参考Born比浊法测定目标化合物的抗血小板聚集活性。结果：设计合成了24个6-(4′-取代酰胺基苯基)-4,5-二氢-3(2H)-哒嗪酮类化合物,22个为首次报道;所有化合物在体外对ADP诱导的兔血小板聚集均有不同程度的抑制作用,第II类化合物的抑制作用强于第I类化合物,其中I₁,I₃,II₁,II₃,II₄,II₆和II₉的抑制作用均强于对照药CI-930,其中II₁和II₃的抑制作用最强,其IC₅₀约为CI-930的1/10。结论：其中一些化合物显示较强的抗血小板聚集活性,值得进一步研究。     

(E)-1-芳基-2-咪唑乙酮和(E)-1-芳基-2-苯并咪唑乙酮取代苯腙衍生物的合成及其抗真菌活性

根据抗真菌药物的作用机理和构效关系,本文设计合成了61个(E)-1-芳基-2-咪唑乙酮和(E)-1-芳基-2-苯并咪唑乙酮取代苯腙衍生物,其中57个化合物是未知的。初步抑菌试验结果表明,大多数化合物对深部致病真菌具有不同程度的抑菌作用。当苯环上有2,6-Cl₂,2,4-Cl₂,p-Cl,p-NO₂,p-OCH₃,p-SCH₃取代时,抗真菌活性较强,特别是有p-OCH₃取代的化合物(如:13,29,45)抗真菌活性优于或相似于克霉唑,抗菌谱也较广。     

血吸虫病化学治疗的研究——ⅩⅩⅩⅦ.β-(5-硝基-4-溴-2-呋喃)-及β-(4,5-二溴-2-呋喃)丙烯酰胺及其酯类的合成

本文报道β-(4,5-二溴-2-呋喃)-及β-(5-硝基-4-溴-2-呋喃)丙烯酰胺及其酯类衍生物26个的合成。动物筛选结果表明;化合物Ⅲ₆,Ⅲ₈和Ⅲ₁₃对感染日本血吸虫小白鼠有明显的治疗作用。化合物Ⅱ₆有较明显的预防作用。     

抗病毒药物4-取代吡咯[2,3-d]嘧啶开环核苷衍生物的合成

天然吡咯[2,3-d]嘧啶核苷及其5-位取代衍生物为既有抗肿瘤活性又有抗病毒作用的抗生素,然毒性过高,未能成为药物。为降低此类化合物的毒性,并考察其构效关系,以4-氯-吡咯[2,3-d]嘧啶为原料,用钠盐直接甙化法与2-氯甲基-1,3-双苄基-丙三醇缩合,得关键中间体Ⅸ,经氨化、氢解,合成了一系列4-取代吡咯[2,3-d]嘧啶开环核苷衍生物。所得新化合物均经抗病毒活性筛选(HSV-1,Cox B6),只有化合物Ⅺ₆,Ⅺ₇,Ⅺ₉对Cox B6有一定的抑制作用。     

Cardiotonic agents. 3. Synthesis and biological activity of novel 6-(substituted 1H-imidazol-4(5)-yl)-3(2H)-pyridazinones

Several 6-(substituted 1H-imidazol-4(5)-yl)-3(2H)-pyridazinones were synthesized and evaluated for positive inotropic activity. The 1H-imidazol-4-yl regioisomers 4,5-dihydro-6-(1-methyl-2-phenyl-1H-imidazol-4-yl)-3(2H)-pyridazinone (25a) and 6-(1-methyl-2-phenyl-1H-imidazol-4-yl)-3(2H)-pyridazinone (28a) were potent positive inotropic agents. By contrast, the corresponding 1H-imidazol-5-yl regioisomers 25b and 28b were only weak positive inotropic agents. Compounds 25a and 28a were also potent inhibitors of cardiac phosphodiesterase fraction III.     

Cardiotonic agents. 7. Prodrug derivatives of 4-ethyl-1,3-dihydro- 5-[4-(2-methyl-1H-imidazol-1-yl)benzoyl]-2H-imidazol-2-one.

The cardiotonic agent 4-ethyl-1,3-dihydro-5-4-(2-methyl-1H-imidazol-1-yl)benzoyl]-2H- imidazol-2-one (1) was found to have low bioavailability when administered orally to rats and dogs. A series of N-acyl derivatives, an underutilized prodrug of acidic NH compounds, has been synthesized and tested for their ability to improve the oral bioavailability of 1. Reaction of the monosodium salt of 1 with various anhydrides afforded the N-1 monoacylimidazolones with surprisingly high regioselectivity. In addition to the prodrugs, acylation of 1 with propionic or phenylacetic anhydride led to the novel 3H-pyrrolo[1,2-c]imidazole-3,5(2H)-diones 6. The prodrugs showed a significant increase in the partition coefficients with a minor decrease in the aqueous solubility. The benzoyl derivative 4b exhibited the highest stability in both pH 1.5 and 7.4 buffer solutions. Further evaluation of 4b showed rapid conversion to 1 in canine plasma (t1/2 = 38 min), and human plasma (t1/2 = 10 min). Oral studies indicated that the bioavailability of 4b was increased to greater than 75% (compared to less than 20% for 1), and hemodynamic studies demonstrated that the selective inotropic profile of 1 was retained.     

Cardiotonic agents. 2. (Imidazolyl)aroylimidazolones, highly potent and selective positive inotropic agents

A series of 4-alkyl-1,3-dihydro-5-[(1H-imidazolyl)benzoyl]-2H-imidazol-2-ones 9 was synthesized and evaluated in vitro for positive inotropic and cyclic AMP phosphodiesterase inhibitory activity. A wide range of inotropic and enzyme-inhibitory potencies was observed, substitution on the imidazolyl moiety being the major determinant of activity. The 4-ethyl-5-[4-(1H-imidazol-1-yl)benzoyl] congener 9g exhibited the highest potency in vitro. Incorporation of a methyl group at the imidazolyl 2-position gave 9h, which was less potent but remarkably selective in vivo for positive inotropic effects over heart rate and hypotensive effects.     

4-Aroyl-1,3-dihydro-2H-imidazol-2-ones: a new class of cardiotonic agents. 2. Effect of 4-pyridoyl substituents and related compounds

A group of 4-pyridoyl-1,3-dihydro-2H-imidazol-2-ones was prepared and tested for inotropic activity in the anesthetized dog. Positive inotropic effects as well as increases in heart rate and decreases in blood pressure were noted for most of these compounds. One of the compounds (8) is currently undergoing clinical trials for the treatment of congestive heart failure.     

Correlation between inotropic activity and drug plasma levels of a new cardiotonic agent,MDL 19205

The correlation between the positive inotropic action of a new cardiotonic agent, MDL 19205 (4-ethyl-1,3-dihydro-5-(4-pyridinyl-carbonyl)-2H-imidazol-2-one), and plasma concentrations of the compound after administration to anesthetized dogs was examined. MDL 19205 solution was introduced into either the stomach or the duodenum of the pylorus ligated dog. Duodenal administration (1–10 mg/kg) resulted in dose-related increases in MDL 19205 plasma levels accompanied by substantial, dose-related increases in cardiac contractility, while gastric administration (3–30 mg/kg) produced much lower, highly variable plasma levels of MDL 19205 accompanied by minimal levels of cardiotonic activity. Our results indicate that the cardiotonic activity of MDL 19205 in the anesthetized dog is closely correlated with drug plasma concentrations, and that the duodenum is the preferred site of absorption of MDL 19205, with very little of the drug being absorbed through the stomach. Since the dog has previously been shown to be a good predictor of the kinetics of MDL 19205 in man, our results suggest that the cardiotonic activity and plasma conncentrations of MDL 19205 in man will also be closely linked.     

Cardiotonic agents. 5. 1,2-Dihydro-5-[4-(1H-imidazol-1-yl)phenyl]-6-methyl-2-oxo-3- pyridinecarbonitriles and related compounds. Synthesis and inotropic activity

Several 1,2-dihydro-5-(substituted phenyl)-2(1H)-pyridinones were synthesized and evaluated for inotropic activity. 1,2-Dihydro-5-[4-(1H-imidazol-1-yl)phenyl]-6-methyl-2-oxo-3- pyridinecarbonitrile (5a) and the corresponding unsubstituted analogue 14a were the most potent positive inotropic agents in this series. Although the 4,6-dimethyl analogue 6a retained most of the activity of 5a, the 4-methyl analogue 8a was substantially less potent. The synthesis and structure-activity relationships are discussed.     

Nonsteroidal cardiotonics. 3. New 4,5-dihydro-6-(1H-indol-5-yl)pyridazin-3(2H)-ones and related compounds with positive inotropic activities

A series of substituted indolyldihydropyridazinones and related compounds 1-18 were synthesized and evaluated for positive inotropic activity. In rats, most of these indole derivatives produced a dose-related increase in myocardial contractility with little effect on heart rate and blood pressure. Compound 13, 4,5-dihydro-5-methyl-6-(2-pyridin-4-yl-1H-indol-5-yl)pyrazin-3(2H) -one (BM 50.0430), was further investigated in cats. The increase in contractility in this animal model was not mediated via stimulation of beta-adrenergic receptors. After oral administration of 1 mg/kg to conscious dogs, compound 13 and pimobendan were still active after 6.5 h. However, the cardiotonic effect of 13 was at least 2-fold that of pimobendan after this period of time. The structural requirements necessary for optimal cardiotonic activity within this novel class of indole derivatives are a heterocyclic aromatic ring in position 2, a hydrogen or a methyl group in position 3, and a dihydropyridazinone ring system in position 5 of the indole.     

Autoxidation of tetrazepam in tablets: prediction of degradation impurities from the oxidative behavior in solution.

The major route of degradation of tetrazepam (1) is oxidation to 7-chloro-5-(3-keto-cyclohexen-1-yl)-1,3-dihydro-1-methyl-2H-1, 4-benzodiazepin-2-one (3) via the stable 7-chloro-5-(3-hydroperoxy-cyclohexen-1-yl)-1,3-dihydro-1-methyl-2H -1, 4 benzodiazepin-2-one (2). Minor degradation products are 7-chloro-5-(1,2-epoxycyclohexan-1-yl)-1,3-dihydro-1-methyl-2H-1, 4-benzodiazepin-2-one (5) and 7-chloro-1,3-dihydro-1-methyl-2H-1, 4-benzodiazepin-2,5-dione (4), resulting from cleavage of the C-C bond between the cyclohexene ring and the benzodiazepine ring. After 48 h, AIBN (2,2'-azobis[2-methyl-propanenitrile]) in acetonitrile at 40 degrees C produced qualitatively the same impurities as those observed in the stability study of tablets of 1. Other stress tests (thermal stress at 80 degrees C, heavy metal oxidation, hydrogen peroxide, acid-catalyzed oxidation) caused qualitatively different profiles of degradation.     

Cardiotonic agents. 6. Synthesis and inotropic activity of 2,4-dihydro-5-[4-(1H-imidazol-1-yl)phenyl]-3H-pyrazol-3-ones: ring-contracted analogues of imazodan (CI-914)

A series of 2,4-dihydro-5-[4-(1H-imidazol-1-yl)phenyl]-3H-pyrazol-3-ones was synthesized and evaluated for positive inotropic activity. Only compounds with two small alkyl groups at C-4 showed significant activity. The structure-activity relationships for optimal inotropic activity are presented and compared with those of the 4,5-dihydro-3(2H)-pyridazinone series. The phosphodiesterase inhibitory activity is also reported and correlated with the substitution pattern at C-4 in the pyrazolone ring.